In type 2 diabetes (T2D), insulin-stimulated blood flow to skeletal muscle is limited and this attenuates glucose uptake, thus contributing to impaired glucose homeostasis. A detailed understanding of the precipitating factors and mechanisms underlying the defects in vascular insulin action is critical for the development of therapeutic strategies aimed at improving glycemic control and protecting against cardiovascular disease. Based on our most recent preliminary data in animal models, we propose the novel hypothesis that endoplasmic reticulum (ER) stress plays an important role in mediating the impairment in insulin-stimulated blood flow in T2D patients. Specifically, we will test if chemical enhancement of ER function with oral administration of supplement tauroursodeoxycholic acid (TUDCA) increases insulin-stimulated blood flow and leg glucose uptake in T2D patients. TUDCA is a bile acid derivative that has been used to treat cholelithiasis and cholestatic liver disease in human patients. Studies in rodent models demonstrate that TUDCA can act as a chemical chaperone to protect against ER stress and improves glucose tolerance. Whether TUDCA can be used as an add-on pharmacological approach to suppress ER stress and improve vascular insulin actions in T2D patients is unknown. We will combine measures of leg blood flow via Doppler ultrasound, intra-arterial pharmacological blockade of endothelin 1 receptors, and measures of leg glucose uptake during a hyperinsulinemic-euglycemic clamp after 4 weeks of TUDCA treatment in a double-blinded, randomized, placebo controlled crossover study. In addition, continuous glucose monitoring will be used to assess the effects of TUDCA on free-living glycemic control. Collectively, this study will provide novel insight on the mechanisms by which alleviation of ER stress enhances insulin-stimulated blood flow, a regulatory site of glucose disposal and glycemic control largely underappreciated. The contribution of this work is significant as it is the first step in a continuum of research expected to lead to the development of novel therapeutic strategies targeting ER stress for prevention and treatment of vascular insulin resistance and glycemic dysregulation associated with T2D. We are poised to move diabetes research forward in an area currently receiving little attention, despite its importance and clear need for investigation.